Antibodies directed to ricin toxin

Abstract

The invention provides a pharmaceutical composition comprising as an active ingredient a combination of three isolated monoclonal antibodies or any antigen-binding fragment thereof which bind ricin toxin and neutralize its toxic effects, and a pharmaceutically acceptable carrier, excipient or diluent. The invention also provides a method of prophylaxis, treatment or amelioration of ricin toxin poisoning including administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition.

The invention claimed is: 
     
       1. A pharmaceutical composition comprising as an active ingredient a combination of at least two isolated monoclonal antibodies or any antigen-binding fragment thereof which bind to ricin toxin, and a pharmaceutically acceptable carrier, excipient or diluent, wherein said antibodies are selected from the group consisting of:
 a. a monoclonal antibody comprising a heavy chain complementarity determining region (CDRH) 1 denoted by SEQ ID NO. 93, CDRH2 denoted by SEQ ID NO. 94, CDRH3 denoted by SEQ ID NO. 95, and the light chain complementarity determining region (CDRL) 1 denoted by SEQ ID NO. 123, a CDRL2 denoted by SEQ ID NO. 124, and a CDRL3 denoted by SEQ ID NO. 125; 
 b. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 114, CDRH2 denoted by SEQ ID NO. 115, CDRH3 denoted by SEQ ID NO. 116, and a CDRL1 denoted by SEQ ID NO. 144, a CDRL2 denoted by SEQ ID NO. 145, and a CDRL3 denoted by SEQ ID NO. 146; and 
 c. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 120, CDRH2 denoted by SEQ ID NO. 121, CDRH3 denoted by SEQ ID NO. 122, and a CDRL1 denoted by SEQ ID NO. 150, a CDRL2 denoted by SEQ ID NO. 151, and a CDRL3 denoted by SEQ ID NO. 152. 
 
     
     
       2. The pharmaceutical composition according to  claim 1 , wherein said isolated monoclonal antibodies are selected from a group consisting of:
 a. a monoclonal antibody comprising a heavy chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 73 and a light chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 83; 
 b. a monoclonal antibody comprising a heavy chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 80 and a light chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 90; and 
 c. a monoclonal antibody comprising a heavy chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 82 and a light chain variable region comprising the amino acid sequence denoted by SEQ ID NO. 92. 
 
     
     
       3. The pharmaceutical composition according to  claim 1 , wherein said composition comprises the isolated monoclonal antibodies:
 a. a monoclonal antibody comprising a heavy chain complementarity determining region (CDRH) 1 denoted by SEQ ID NO. 93, CDRH2 denoted by SEQ ID NO. 94, CDRH3 denoted by SEQ ID NO. 95, and the light chain complementarity determining region (CDRL) 1 denoted by SEQ ID NO. 123, a CDRL2 denoted by SEQ ID NO. 124, and a CDRL3 denoted by SEQ ID NO. 125; 
 b. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 114, CDRH2 denoted by SEQ ID NO. 115, CDRH3 denoted by SEQ ID NO. 116, and a CDRL1 denoted by SEQ ID NO. 144, a CDRL2 denoted by SEQ ID NO. 145, and a CDRL3 denoted by SEQ ID NO. 146; and 
 c. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 120, CDRH2 denoted by SEQ ID NO. 121, CDRH3 denoted by SEQ ID NO. 122, and a CDRL1 denoted by SEQ ID NO. 150, a CDRL2 denoted by SEQ ID NO. 151, and a CDRL3 denoted by SEQ ID NO. 152 
 
       and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
       4. The pharmaceutical composition according to  claim 1 , wherein said composition consists of the isolated monoclonal antibodies
 a. a monoclonal antibody comprising a heavy chain complementarity determining region (CDRH) 1 denoted by SEQ ID NO. 93, CDRH2 denoted by SEQ ID NO. 94, CDRH3 denoted by SEQ ID NO. 95, and the light chain complementarity determining region (CDRL) 1 denoted by SEQ ID NO. 123, a CDRL2 denoted by SEQ ID NO. 124, and a CDRL3 denoted by SEQ ID NO. 125; 
 b. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 114, CDRH2 denoted by SEQ ID NO. 115, CDRH3 denoted by SEQ ID NO. 116, and a CDRL1 denoted by SEQ ID NO. 144, a CDRL2 denoted by SEQ ID NO. 145, and a CDRL3 denoted by SEQ ID NO. 146; and 
 c. a monoclonal antibody comprising the CDRH1 denoted by SEQ ID NO. 120, CDRH2 denoted by SEQ ID NO. 121, CDRH3 denoted by SEQ ID NO. 122, and a CDRL1 denoted by SEQ ID NO. 150, a CDRL2 denoted by SEQ ID NO. 151, and a CDRL3 denoted by SEQ ID NO. 152 
 
       and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
       5. The pharmaceutical composition according to  claim 1 , wherein said isolated monoclonal antibodies are chimeric, humanized or human antibodies. 
     
     
       6. The pharmaceutical composition according to  claim 1 , wherein said isolated monoclonal antibodies are chimeric antibodies. 
     
     
       7. The pharmaceutical composition according to  claim 1 , wherein said isolated monoclonal antibodies are antibody fragments selected from the group consisting of Fv, single chain Fv (scFv), heavy chain variable region, light chain variable region, Fab, F(ab)2′ and any combination thereof. 
     
     
       8. The pharmaceutical composition according to  claim 1 , wherein said isolated monoclonal antibodies are neutralizing antibodies. 
     
     
       9. The pharmaceutical composition according to  claim 1 , wherein said composition further comprising an adjuvant. 
     
     
       10. The pharmaceutical composition according to  claim 1 , wherein said composition further comprises an additional anti-ricin agent. 
     
     
       11. A method of prophylaxis, treatment or amelioration of ricin toxin poisoning comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to  claim 1 . 
     
     
       12. The method according to  claim 11 , wherein said method further comprises administering to a subject in need thereof an additional anti-ricin agent. 
     
     
       13. The method according to  claim 11 , wherein said pharmaceutical composition is administered to said subject prior to or after exposure to ricin toxin. 
     
     
       14. The method according to  claim 13 , wherein said pharmaceutical composition is administered to said subject immediately after exposure to ricin toxin or between about 1 to about 96 hours after exposure to ricin toxin. 
     
     
       15. The method according to  claim 11 , wherein said isolated monoclonal antibodies in the pharmaceutical composition are administered at a therapeutically effective amount of 10-50,000 μg/kg. 
     
     
       16. The method according to  claim 11  wherein said pharmaceutical composition is administered to said subject as a single dose or as multiple doses.